Beta-lactam antibiotic-containing tablet and production thereof

ABSTRACT

This invention provides β-lactam antibiotic-containing tablets capable of being orally taken either as such owing to their being small-sized, hence still easily swallowable, or, in the case of administration to the aged encountering some difficulty in swallowing, in the form of dispersions resulting from easy self-disintegration upon being dropped into water in a glass as well as a method of producing the same. The tablets of this invention comprise, on the per-tablet basis, 60-85% by weight of a β-lactam antibiotic, 1-10% by weight of low-substituted hydroxypropylcellulose and/or crosslinked polyvinylpyrrolidone as a disintegrator, and 0.5-2% by weight of a binder. Granules to be compressed for tableting are prepared using water or an aqueous solution of ethanol or the like.

TECHNICAL FIELD

[0001] This invention relates to β-lactam antibiotic-containing tabletsand a method of producing the same. More particularly, it relates totablets of the above variety which can be orally taken either as suchor, for taking by, for example, the aged who have difficulties inswallowing, as a dispersion available upon dropping the same into waterin a glass for self-disintegration, and to a method of producing thesame.

BACKGROUND TECHNOLOGY

[0002] Particularly in Europe and America, where β-lactam antibioticssuch as cefixime and cefdinir are administered generally in single dosesof as great as 200 mg to 400 mg potency, unit dosage forms, whether theyare capsules or tablets, have to be considerably large in size. When 400mg potency capsules are prepared, for instance, the capsule size reachesapproximately No. 0, so that not only patients having difficulties inswallowing but also ordinary adult patients become reluctant to takethem or get a repulsive sensation in taking them. Such capsules areindeed difficult to take. In the case of tablets, too, 400 mg potencytablets generally weigh 700 to 1,000 mg per tablet and accordingly arelarge-sized.

[0003] The problems encountered in taking such large dosage forms givean unnecessary sensation of oppression to patients on the occasion oftaking them. Improvements in their administrability have thus beenrequired.

[0004] Therefore, the present inventor attempted to provide a dosageform with improved administrability by reducing the tablet size as muchas possible to thereby facilitate the taking of tablets by the recipientand at the same time to provide a dosage form capable of being taken inthe form of a dispersion resulting from rapid self-disintegration uponits being simply dropped into water or the like in a glass, forinstance, to thereby make said dosage form administrable to persons ofadvanced age or children having difficulties in swallowing the dosageform as such. The expression “rapid self-disintegration” as used hereinmeans that when the preparation is dropped into a glass containing aliquid such as water, the tablet form spontaneously collapses generallywithin 3 minutes, preferably within 1 minute, so that said preparationcan be orally taken in dispersion form without awaiting long beforetaking.

[0005] It is indeed easy to produce tablets capable ofself-disintegrating very rapidly by incorporating an effervescent agentcomprising a combination of sodium hydrogen carbonate and tartaric acid,for instance. However, when such tablets are orally taken, they give offbubbles in the oral cavity, so that patients feel a discomfort or anunnecessary sensation of anxiety. For securing a good shelf-life in ahumid environment, it is necessary to use a moisture-proof packagingmaterial, which increases the production cost. Therefore, in developingthe dosage form which the present invention is intended to provide, ithas been a tough problem to find out a formulation enabling very rapidself-disintegration without the aid of any effervescent component.

[0006] For producing β-lactam antibiotic-containing tablets which can beeasily ingested as they are and be also ingested in the form of adispersion resulting from self-disintegration thereof, a technology isdescribed in European Patent EP 0281200 B (corresponding Japanese patentapplication: Kokai Tokkyo Koho S63-301820), which comprises adding 24 to70% by weight, based on the weight of the β-lactam antibiotic, ofmicrocrystalline cellulose or microfine cellulose as a firstdisintegrator and 2 to 20% by weight, on the same basis, oflow-substituted hydroxypropylcellulose or the like as a seconddisintegrator.

[0007] However, said first disintegrator, which is used in a largeamount, increases the tablet size. In addition, the proportion of abinder component for wet granulation is as low as 0 to 0.1% by weightbased on the antibiotic, hence is substantially nil. This is because theuse of a binder renders tablets extremely poor in self-disintegratingproperties. In the process for producing these tablets, in which nobinder is used, a special method of insuring an integrity of theartefact is employed which comprises mixing the antibiotic bulksubstance with microcrystalline cellulose and kneading the mixture withthe aid of water under application of a great deal of force, withoutusing any alcohol. As a result, large lumps are formed inevitably andthey are milled in the wet state and then dried, followed by furthermilling to provide granules for tableting. It is a problem that thesesteps are very inefficient.

[0008] Meanwhile, tablets containing amoxicillin, which is a β-lactamantibiotic, are commercially available under the trade name of FlemoxinSolutab 500 from Brocades Pharma (Netherlands), the patentee to whomsaid European patent has been granted. Said tablets each contains 500 mgpotency (about 570 mg) of amoxicillin and weighs about 970 mg, hence isvery large and not entirely suited for oral administration.

[0009] Most β-lactam antibiotics are bitter. Therefore, aqueousdispersions prepared from tablets containing them, when orally taken,give a bitter taste, although the tablets, when taken as such, taste notso bitter. For masking the bitter taste, it thus becomes necessary toincorporate a sweetener, preferably a synthetic sweetener which iseffective at low addition levels and thus suited for tabletminiaturization. However, when a commercial synthetic sweetener isincorporated, a problem arises, namely the self-disintegratingproperties of tablets become poor, since synthetic sweeteners aresoluble in water and become viscous and sticky.

DISCLOSURE OF THE INVENTION

[0010] In an attempt to develop a method of improving the rate ofself-disintegration of tablets and at the same time miniaturizing thesame, the present inventor made investigations concerning thedisintegrator species to be used, the level of addition thereof, thebinder addition level, the synthetic sweetener particle size and themethod of incorporating the same, among others and, as a result, theinventor invented β-lactam antibiotic-containing tablets which aresmall-sized, show good self-disintegrating properties and can beproduced by a conventional method.

[0011] Furthermore, the inventor found that when granulation isperformed using ethanol, isopropyl alcohol or an aqueous solution ofethanol or isopropyl alcohol, tablets showing better dispersibility uponself-disintegration can be obtained.

[0012] The β-lactam antibiotic-containing tablets of this inventioncontain, per tablet, 60 to 85% by weight of an β-lactam antibiotic, 1 to10% by weight of low-substituted hydroxypropylcellulose and/orcrosslinked polyvinylpyrrolidone as a disintegrator, and 0.5 to 2% byweight of a binder.

[0013] Preferably, the β-lactam antibiotic-containing tablets of thisinvention further contain, per tablet, 0.5 to 15% by weight of asynthetic sweetener and/or a granulated synthetic sweetener.

[0014] The β-lactam antibiotic-containing tablet production method ofthis invention is characterized in that the above-specified respectiveproportions of a β-lactam antibiotic, the disintegrator and a binder,optionally together with one or more excipients, are granulated usingethanol, isopropyl alcohol or an aqueous solution of ethanol orisopropyl alcohol, the granulation product is mixed with theabove-specified proportion of a synthetic sweetener and/or a granulatedsynthetic sweetener, optionally together with one or more otheradditives, and the resulting mixture is compressed.

[0015] The β-lactam antibiotic to be used in the practice of thisinvention is one capable of producing a beneficial effect upon oraladministration and includes, for example, cefixime and cefdinirrespectively represented by the structural formulas shown below as wellas cefaclor, cefroxadine, cefadroxil, cefaloglycin, cefalexin,cefradine, amoxicillin, ampicillin and the like.

[0016] Each tablet contains such β-lactam antibiotic in a proportion of60 to 85% by weight, preferably 65 to 80% by weight.

[0017] As a result of investigations concerning the disintegratorspecies to be used in the practice of this invention and the level ofaddition thereof, it was found that, as compared with such salt typedisintegrators as ECG 505 (trademark; carboxymethylcellulose calcium),Ac-Di-Sol (trademark; crosslinked carboxymethylcellulose sodium) andPrimojel (trademark; starch glycolic acid sodium), nonion typedisintegrators, such as low-substituted hydroxypropyl-cellulose (L-HPC)and crosslinked polyvinylpyrrolidone, can produce a very gooddisintegrating effect even when they are added in small proportions.Low-substituted hydroxypropylcellulose is a product derived fromcellulose by partial substitution with the 2-hydroxypropoxy group, thedegree of substitution being not higher than 25%, preferably 7 to 16%.

[0018] Generally, low-substituted hydroxypropylcellulose and crosslinkedpolyvinylpyrrolidone are incorporated in tablets independently, althoughboth may be used combinedly.

[0019] Such disintegrator is used in a proportion of 1 to 10% by weight,preferably 3 to 8% by weight, on a per-tablet basis.

[0020] The tablets of this invention further contain binder as anessential constituent. The addition of a binder has an adverse effect onthe self-disintegrating properties of tablets, hence is not desirablefrom the self-disintegration viewpoint. However, the production oftablets without adding any binder give such inconveniences as mentionedherein-before.

[0021] The inventor of this invention made investigations in search ofbinder species which would not give adverse effects on theself-disintegrating properties of tablets as well as investigationsconcerning the addition level thereof. As preferred binders, there maynow be mentioned, for example, polyvinylpyrrolidone,hydroxypropylcellulose, preferably low-viscosity type (L-type)hydroxypropylcellulose, hydroxy-propylmethylcellulose, methylcellulose,starch, pregelatinized starch, partly pregelatinized starch, gum arabic,dextrin, pullulan and the like. Among these binders,polyvinylpyrrolidone, hydroxypropylcellulose andhydroxypropylmethylcellulose are more preferred, andpolyvinylpyrrolidone is most preferred. When these binders are used inan amount of 0.5 to 2% by weight, preferably 0.8 to 1.5%by weight, on aper-tablet basis, tablets which can self-disintegrate rapidly can beproduced by a conventional production method.

[0022] Since β-lactam antibiotics, for example cefixime and cefdinir,have a strongly bitter taste, it is necessary to add a syntheticsweetener in cases where tablets are to be taken in the form ofdispersions after self-disintegration in water, for instance, thoughthis is not always necessary in cases where tablets are to be taken assuch.

[0023] As regards the synthetic sweetener addition level, which may varyaccording to the synthetic sweetener species and the active ingredientβ-lactam antibiotic, the sweetener is incorporated in tablets generallyin a proportion of 0.5 to 15% by weight, preferably 1 to 10% by weight.

[0024] The commercial synthetic sweetener products are generally small,i.e. less than 150 μm, in mean particle size, with particle not smallerthan 150 μm accounting for at most 4% of the whole. Incorporation ofsuch products markedly reduces the rate of disintegration of tablets. Toimprove the disintegration rate, the prior art employs a method whichcomprises incorporating a large amount of an excipient such asmicrocrystalline cellulose. However, incorporation of a large amount ofsuch excipient according to said method results in an increase in tabletsize, thereby making the tablets difficult to take with ease. Thepresent inventor found that when the particle size of a syntheticsweetener is increased or when a granulated mixture of a syntheticsweetener and light anhydrous silicic acid, hydrated silicon dioxide orthe like is added, the rate of disintegration can be improved, namelyprevented from retardation.

[0025] As a result, an invention was made of miniaturized tablets whichcan be easily taken as such and, when dropped into water in a glass, canrapidly self-disintegrate, enabling administration thereof in dispersionform.

[0026] When such a synthetic sweetener as saccharin, a salt thereof(e.g. saccharin calcium, saccharin sodium), cyclamic acid or a saltthereof (e.g. sodium cyclamate, calcium cyclamate, ammonium cyclamate)is used, said sweetener is required to be not less than 150 μm in meanparticle size, preferably not less than 150 μm in particle size. In thecase of a sweetener capable of producing a satisfactory bitter-maskingeffect in small amounts, for example aspartame, it is not alwaysnecessary that the mean particle size be not less than 150 μm, since thedisintegrability of tablets is little affected.

[0027] The synthetic sweetener may be incorporated either in the form ofcrystalline grains having a mean particle size of not less than 150 μmor in the form of a granulation product meeting the particle sizerequirement as obtained by wet granulation from the powder form small inmean particle size or by wet granulation or dry granulation from suchpowder together with a color additive and/or microcrystalline celluloseor a like excipient.

[0028] The granulation product containing light anhydrous silicic acidor hydrated silicon dioxide in addition to a synthetic sweetener can beproduced by mixing the synthetic sweetener with 1 to 30% by weight,relative to the synthetic sweetener weight, of light anhydrous silicicacid or hydrated silicon dioxide and granulating the mixture in theconventional manner, if necessary using a binder and/or one or moreother additives in common use. It was found that in the case ofgranulation products containing a synthetic sweetener together withlight anhydrous silicic acid or hydrated silicon dioxide, the particlesize is not critical, with the result that the self-disintegratingproperties are never adversely affected even when the mean particle sizeis below 150 μm. As regards other ingredients to be used in producingthe tablets of this invention, the same ingredients or additives as usedconventionally in the production of solid preparations may be mentioned.Thus, in addition to the above-mentioned synthetic sweetener orgranulated synthetic sweetener, excipients such as microcrystallinecellulose, lactose, mannitol, starch, etc., flowability improvers suchas light anhydrous silicic acid, hydrated silicon dioxide, etc.,lubricants such as magnesium stearate, stearic acid, talc, etc.,flavoring agents and other agents may be incorporated unless theself-disintegrating properties are adversely affected. When the β-lactamantibiotic has a large particle size, it may be ground prior to use. Inthis case, however, wet or dry granulation is required to improve thepowder flowability in the step of compression.

[0029] In a preferred process for producing the tablets of the presentinvention, the above-specified disintegrator and binder, optionallytogether with other ingredients, are added to the β-lactam antibiotic,the mixture is granulated by a conventional method, the above-mentionedsynthetic sweetener and/or granulated synthetic sweetener, optionallytogether with one or more other ingredients (e.g. flowability improver,lubricant, flavor), are then further added, and the resulting mixture issubjected to tableting.

[0030] When, in the above production process, water is used forgranulation in the granulation step, tablets with goodself-disintegrating properties are generally obtained. In thisconnection, the inventor of this invention further found that whenethanol, isopropyl alcohol or a mixture of water and ethanol orisopropyl alcohol is used for granulation, tablets with goodself-disintegrating properties and with very good dispersibility uponallowing dispersion in water can be obtained. The concentration of theaqueous solution of ethanol or isopropyl alcohol, which is suited foruse, is 3 to 99% (volume/volume), preferably 10 to 60% (volume/volume).

INDUSTRIAL APPLICABILITY

[0031] The thus-obtained β-lactam antibiotic-containing tablets of thisinvention are small in size. For example, a tablet containing 400 mgpotency (about 449 mg) of cefixime may weigh not more than 650 mg and atablet containing 300 mg potency (about 307 mg) of cefdinir not morethan 450 mg. They can be orally taken as such with ease. When they areto be taken by the aged, for instance, complaining of some difficulty inswallowing, in an aqueous dispersion form, the tablets can be rapidlydisintegrated and dispersed in water.

[0032] Moreover, the use of ethanol, isopropyl alcohol or an aqueoussolution of ethanol or isopropyl alcohol for granulation in thegranulation step makes it possible to obtain tablets with still betterdispersibility in water.

Test Example 1 Disintegrator Effect

[0033] According to the formulation shown below in Table 1, cefiximebulk substance, microcrystalline cellulose, one of the disintegrators,light anhydrous silicic acid and magnesium stearate, taken in therespective specified proportions, were mixed up and the mixture wascompressed on a single-punch tablet machine to give tablets having adiameter of 11 mm.

[0034] The tablets produced by the above method were evaluated fordisintegration time in 1,000 ml of water (20±1° C.) using a JapanesePharmacopeia disintegration tester, but without using any disk, with 30cycles per minute of basket ascending and descending. The disintegrationtime data thus obtained are shown in Table 2. TABLE 1 Cefixime bulksubstance 448.9 (400 mg potency) Microcrystalline cellulose 38.9Disintegrator 38.9 Light anhydrous silicic acid 1.2 Magnesium stearate5.9 Total 533.8 mg

[0035] TABLE 2 Disintegration time Disintegrator (min.) n = 6Carboxymethylcellulose 1.2-1.3 calcium Starch glycolic acid 1.0-1.2sodium Crosslinked carboxymethyl- 0.8-1.1 cellulose sodiumLow-substituted 0.3-0.4 hydroxypropylcellulose Crosslinked polyvinyl0.3-0.4 pyrrolidone

[0036] As is evident from Table 2, those tablets which containlow-substituted hydroxypropylcellulose or crosslinkedpolyvinylpyrrolidone in accordance with the present inventiondisintegrate very rapidly.

Test Example 2 Binder Study

[0037] According to the formulation shown below in Table 3, cefiximebulk substance micronized by a pin-type mill, microcrystalline celluloseand one of the binders, together with 50% (by volume) ethanol, weregranulated in a high speed shear mixer, followed by drying under flowingair at 40° C. for 17 hours and sizing through a 500-μm sieve. Thegranules sieved out were mixed with low-substitutedhydroxypropylcellulose, light anhydrous silicic acid and magnesiumstearate, in the respective specified proportions, followed bycompression on a single-punch tablet machine, to give tablets eachhaving the specified weight and a diameter of 11 mm.

[0038] The tablets produced by the above method were evaluated fordisintegration time under the same conditions as in Test Example 1. Thedisintegration time data thus obtained are shown in Table 4. TABLE 3Cefixime 448.9 (400 mg potency) Microcrystalline cellulose 38.9 Binder4.9 (14.6) Low-substituted hydroxypropylcellulose 38.9 Light anhydroussilicic acid 1.2 Magnesium stearate 5.9 Total 538.7 mg (548.4 mg)

[0039] TABLE 4 % addition level Disintegration time Binder (weight inmg) (min.) n = 6 Polyvinylpyrrolidone 0.9 (4.9)  0.6-0.8Polyvinylpyrrolidone 2.7 (14.6) 2.1-2.1 Hydroxypropylcellulose 0.9(4.9)  1.4-2.0 (L type) Hydroxypropylmethyl- 0.9 (4.9)  1.0-1.5cellulose

[0040] As is evident from Table 4, the tablets produced by usingpolyvinylpyrrolidone, hydroxypropylcellulose (L type) orhydroxypropylmethylcellulose as the binder disintegrate rapidly.

Test Example 3 Synthetic Sweetener Particle Size Study

[0041] According to the formulation shown below in Table 5, cefiximebulk substance micronized by a pin-type mill, microcrystallinecellulose, low-substituted hydroxypropylcellulose andpolyvinylpyrrolidone, together with 50% (by volume) ethanol, weregranulated in a high speed shear mixer, followed by drying under flowingair at 40° C. for 17 hours and sizing using a 500-μm sieve. The granulessieved out were mixed with light anhydrous silicic acid, magnesiumstearate, strawberry powder flavor and commercial saccharin calcium, thelarge particle size saccharin calcium prepared in Example 1 to bementioned later herein or the granulated mixture of saccharin calciumand light anhydrous silicic acid prepared in Example 2 to be mentionedlater herein, in the respective specified proportions, followed bycompressing on a single-punch tablet machine to give tablets each havingthe specified weight and a diameter of 11 mm.

[0042] The tablets produced by the above method were evaluated fordisintegration time under the same conditions as in Test Example 1. Thedisintegration time data thus obtained are shown in Table 6. TABLE 5Cefixime 448.9 (400 mg potency) Microcrystalline cellulose 38.9Low-substituted 38.9 hydroxypropylcellulose Polyvinylpyrrolidone 4.9Light anhydrous silicic acid 1.2 Magnesium stearate 5.9 Strawberrypowder flavor 7.5 Saccharin calcium or 20.0 granulated saccharin calciumTotal 566.2 mg

[0043] TABLE 6 Mean disintegration Synthetic sweetener time (min.), n =6 Saccharin calcium 3.0 (mean particle size < 150 μm) Saccharin calcium0.6 (particle size 150-840 μm) Saccharin calcium-light anhydrous 1.3silicic acid mixture granulated (particle size 75-500 μm)

[0044] As is evident from Table 6, the tablets produced by using thesaccharin calcium not less than 150 μm in particle size or thegranulated mixture of saccharin calcium and light anhydrous silicic acidare positively shorter in disintegration time than the tablets producedby using the commercial saccharin calcium smaller than 150 μm in meanparticle size.

Test Example 4 Influence of the Composition of the Solution forGranulation on the Dispersibility of Tablets

[0045] A 2,200 ml portion of water or an aqueous solution of ethanol wasused to granulate a mixture of 4,566 g of cefixime bulk substancemicronized by a pin-type mill, 405 g of microcrystalline cellulose, 405g of low-substituted hydroxypropylcellulose and 50.6 g ofpolyvinylpyrrolidone in a high speed shear mixer and, after drying underflowing air at 40°-0 C. for 17 hours, the granulation product was sizedusing a 500-μm sieve. The granules sieved out were mixed with 50.6 g oflight anhydrous silicic acid, 101.2 g of magnesium stearate, 75.9 g ofstrawberry powder flavor and 202.6 g of saccharin calcium (particlesize: 150-840 μm), followed by compressing on a rotary tablet machine togive oblong tablets each weighing 579 mg.

[0046] The tablets produced by the above method were evaluated, by themethod mentioned below, for disintegration time as well as fordispersibility for use in dispersion form. Disintegration time

[0047] The disintegration time evaluation was made in 1,000 ml of water(20±1° C.) using a Japanese Pharmacopeia disintegration tester, butwithout using any disk, with 30 cycles per minute of basket ascendingand descending. Dispersibility after standing of dispersions prepared

[0048] One tablet was dropped into 20 ml of water placed in a 50-mlbeaker and the whole was allowed to stand for 5 minutes forself-disintegration. Then, the beaker was shaken gently for stirring andthereafter allowed to stand for 1 minute, followed by observation of theappearance. TABLE 7 Disintegration Dispersibility time (sec.) afterstanding Granulation 39 a using 50% ethanol Granulation 84 a using 10%ethanol Granulation 62 b using water Flemoxin Solutab 500 46 b(commercial product)

[0049] The tablets derived from the granules prepared using ethanol arestill better in dispersibility after standing as compared with thosederived from the granules prepared using water.

Test Example 5 Disintegration Test

[0050] Test preparations A: Tablets produced in Example 1 to bementioned later. B: Tablets produced in Example 7 to be mentioned later.C: Tablets produced in Example 8 to be mentioned later.

[0051] Test method

[0052] The disintegration time evaluation was performed in distilledwater at 20±1° C. with 4 cycles per minute of basket ascending anddescending, using an apparatus prescribed in the Japanese Pharmacopeia(12th edition) under Disintegration Test.

[0053] Test Results

[0054] A: 1.13 minutes

[0055] B: 1.30 minutes

[0056] C: 1.02 minutes

[0057] The disintegration test results indicate that the testpreparations A to C of this invention each shows good disintegrability.

EXAMPLE Example 1

[0058] Water was added to saccharin calcium and the mixture wasgranulated by a conventional method, followed by drying, sieving andsizing to give saccharin calcium granules not less than 150 μm inparticle size.

[0059] According to the formulation shown below, micronized cefiximebulk substance, microcrystalline cellulose, low-substitutedhydroxypropylcellulose (L-HPC) and polyvinylpyrrolidone were weighed andmixed together, water was then added, and the mixture was granulated.The granulation product was dried under flowing air at 40° C. for 17hours and then sized using a 500-μm sieve. The granules sieved out weremixed with magnesium stearate, light anhydrous silicic acid, strawberryflavor and the above-mentioned granulated saccharin calcium according tothe formulation shown below, followed by compressing on a single-punchtablet machine to give tablets each having the specified weight. TABLE 8Micronized cefixime bulk substance 448.9 mg (400 mg potency)Microcrystalline cellulose 38.9 mg (Avicel ™ PH101; Asahi ChemicalIndustry) L-HPC (LH-21; Shin-Etsu Chemical) 38.9 mg Polyvinylpyrrolidone4.9 mg (Kollidon ™ 30; BASF) Light anhydrous silicic acid 1.2 mg(Aerosil ™; Tomita Seiyaku) Magnesium stearate 5.9 mg Saccharin calcium20.0 mg (not less than 150 μm particle size) Strawberry flavor 7.5 mgTotal 566.2 mg

Example 2

[0060] Saccharin calcium and light anhydrous silicic acid were mixedtogether in a ratio of 20:1 and then water was added. The resultantmixture was granulated by a conventional method, followed by drying andsizing to give a granulated mixture of saccharin calcium and lightanhydrous silicic acid (75-500 μm in particle size).

[0061] Then, tablets were produced following the procedure of Example 1except that 21 mg of the above granulated mixture was used in lieu of 20mg of saccharin calcium (Example 1, Table 8).

Example 3

[0062] Saccharin calcium and hydrated silicon dioxide were mixedtogether in a ratio of 20:1 and then water was added. The resultantmixture was granulated by a conventional method, followed by drying andsizing to give a granulated mixture of saccharin calcium and hydratedsilicon dioxide (75-500 μm in particle size).

[0063] Then, tablets were produced following the procedure of Example 1except that 21 mg of the above granulated mixture was used in lieu of 20mg of saccharin calcium (Example 1, Table 8).

Example 4

[0064] Tablets each containing 400 mg (potency) of cefixime wereproduced in the same manner as in Example 1 except that L-HPC of Example1 (Table 8) was replaced by the same amount of crosslinkedpolyvinylpyrrolidone (Kollidon™ CL; BASF).

Example 5

[0065] Tablets each containing 400 mg (potency) of cefixime wereproduced in the same manner as in Example 1 except thatpolyvinylpyrrolidone of Example 1 (Table 8) was replaced by the sameamount of hydroxypropylcellulose (HPC-L; Nippon Soda).

Example 6

[0066] Tablets each containing 400 mg (potency) of cefixime wereproduced in the same manner as in Example 1 except thatpolyvinylpyrrolidone of Example 1 (Table 8) was replaced by the sameamount of hydroxypropylmethylcellulose (TC-5R™; Shin-Etsu Chemical).

Example 7

[0067] According to the same formulation as that shown in Example 1(Table 8), micronized cefixime bulk substance, microcrystallinecellulose, L-HPC and polyvinylpyrrolidone were weighed and mixedtogether, 50% aqueous ethanol was added, and the mixture was granulated.The granulation product was dried under flowing air at 40° C. for 17hours and then sized using a 500-μm sieve. The granules sieved out weremixed with magnesium stearate, light anhydrous silicic acid, strawberryflavor and the granulated saccharin calcium prepared in Example 1 (notless than 150 μm in particle size) and the resultant mixture wascompressed on a single-punch tablet machine to give tablets having thesame composition as that in Example 1 (Table 8).

Example 8

[0068] According to the formulation shown below, cefdinir-containingtablets were produced in the same manner as in Example 7. TABLE 9Micronized cefdinir bulk substance 306.8 mg (300 mg potency)Microcrystalline cellulose (Avicel PH101) 29.2 mg L-HPC (LH-21) 29.2 mgPolyvinylpyrrolidone (Kollidon 30) 3.7 mg Light anhydrous silicic acid(Aerosil) 0.9 mg Magnesium stearate 4.4 mg Saccharin calcium 15.0 mg(not less than 150 μm in particle size) Strawberry flavor 5.6 mg Total394.8 mg

What is claimed is:
 1. A β-lactam antibiotic-containing tablet whichcomprises 60 to 85% by weight of a β-lactam antibiotic, 1 to 10% byweight of low-substituted hydroxypropylcellulose and/or crosslinkedpolyvinylpyrrolidone as a disintegrator and 0.5 to 2% by weight of abinder per tablet.
 2. A tablet as claimed in claim 1, wherein the binderis polyvinylpyrrolidone, hydroxypropylcellulose orhydroxypropylmethylcellulose.
 3. A tablet as claimed in claim 1 or 2which further comprises 0.5 to 15% by weight of a synthetic sweetenerand/or a granulated synthetic sweetener.
 4. A tablet as claimed in claim3, wherein the synthetic sweetener or the granulated synthetic sweetenerhas an mean particle size of not less than 150 μm.
 5. A tablet asclaimed in claim 4, wherein the synthetic sweetener or the granulatedsynthetic sweetener is not less than 150 μm in particle size.
 6. Atablet as claimed in claim 3, wherein the granulated synthetic sweetenercomprises a synthetic sweetener, and light anhydrous silicic acid and/orhydrated silicon dioxide.
 7. A tablet as claimed in any of claims 1 to6, wherein the β-lactam antibiotic is cefixime or cefdinir.
 8. A tabletas claimed in claim 7 which contains 400 mg potency of cefixime, thetablet weight being not greater than 650 mg.
 9. A tablet as claimed inclaim 7 which contains 300 mg potency of cefdinir, the tablet weightbeing not greater than 450 mg.
 10. A method of producing β-lactamantibiotic-containing tablets which comprises admixing a syntheticsweetener and/or a granulated synthetic sweetener, optionally togetherwith one or more other additives, with a granulation product preparedfrom the β-lactam antibiotic, disintegrator and binder specified inclaim 1, optionally together with one or more excipients, by usingethanol, isopropyl alcohol or an aqueous solution of ethanol orisopropyl alcohol, and then tableting the resulting mixture.